Abstract

Genetic polymorphisms in drug-metabolizing enzymes have been linked to inter-individual differences in the efficacy and toxicity of many medications. The aim of our study was to reveal the association of MTHFR and GSTP1 gene polymorphisms with toxicity in breast cancer patients treated with adjuvant anthracycline-based treatment. The case group comprised 74 patients with breast cancer (median age: 48.9, range: 2769 years; stage: II-III). All patients received 6 cycles of adjuvant anthracycline-based chemotherapy regimen with 5-fluorouracil, adriamycin, and cyclophosphamide (FAC). Toxicity was assessed using NCI-CTC. The polymorphic variants of the MTHFR (c. 677 C>T) and GSTP1 (c. 313 A>G) were analyzed by Allelic Discrimination Real Time PCR using specific primers and TaqMan MGB probes. The genotypes distributions observed were similar to Hardy-Weinberg equilibrium expectations. The association between genotypes and toxicity was tested using univariate logistic regression and logistic regression analysis adjusted for sex, age and comorbidity. During chemotherapy breast cancer patients developed some degree of gastrointestinal, hematological, cardiovascular and neurotoxicity. The most frequent cases of toxicity were observed after 2nd cycle with futher increase in the following cycles. No toxic deaths were registered. Cardiovascular toxicity occured in 24.3 of patients. Logistic regression have shown that cardiovascular toxicity was overrepresented among patients with the MTHFR T677T genotype with an odds ratio (OR) 5.77 [95CI1.5022.17, P0.01]. Severe gastrointestinal toxicity developed in 48 of the cases. The predominant gastrointestinal toxicity types were nausea (95), vomiting (31). It was noticed that homozygous carriers of the 313G allele variant have a significantly higher risk for gastrointestinal toxicity with OR 10,57 [95CI1.2589.50, P0.03). Haematological toxicity GIII-IV occurred in 9.4 of patients. Patients with one or two mutant alleles of MTHFR gene have shown tendency to develop haematological toxicity (P0.09), predominant hematological toxicity type - neutropenia. Our results suggest that GSTP1 and MTHFR polymorphisms may be considered as relevant and independent factors of toxicity in adjuvant anthracycline-based treatment of breast cancer.